The best starting point in treating PCOS? It’s not Clomid.

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To say that PCOS is a huge problem is a real understatement. It affects 6 - 8 % of women, and it’s the most common reason for anovulatory infertility (more than 80% of cases)!

For a long time, Clomiphene Citrate (usually prescribed as Clomid) has been a standard first line drug used to induce ovulation in PCOS. But there’s a big gap in how often Clomid makes women ovulate (about 85% of the time), versus how often it leads to pregnancy (35-40% of the time). It’s hypothesized that this may be because of adverse effects Clomid has on the endometrium and cervical mucus.

A few years ago, a Cochrane systematic review reported that Letrozole (brand name Femara) had a 44% higher pregnancy rate thank Clomid for PCOS women, but the quality of the evidence wasn’t convincing at the time.

New Study: Clomid vs. Femara

Now, a recent study with a much better design has tried to answer the question: which is a better first line ovulation induction method for anovulatory PCOS women -- Clomiphene Citrate (Clomid) or Letrozole (Femara)? They compared ovulation rates, pregnancy, live birth, and more. We’ll spell out more details below, but at a very high level, Femara looked much better than clomid on just about every meaningful outcome.

Study Design

The good news: this was a randomized controlled trial, and it was blinded, meaning the women and the doctors didn’t know which drug they were on. This was a group of 159 women aged 18 - 39 years old, with BMIs of 35 or less. All of them were not ovulating and met the definition of PCOS based on the Rotterdam criteria (which means at least 2 of: anovulation, hyperandrogenaemia, and polycystic ovaries on ultrasound).

Treatment was continued until pregnancy or 6 ovulatory cycles, at which point, if they weren’t pregnant, they were crossed over to the other drug as a secondary option. If they didn’t respond to either treatment earlier, they also had the option to take a 6 week break then cross over.

The Important Stuff: What the Study Showed

Femara showed a significantly higher pregnancy rate than Clomid -- the rate was 61%, which was 40% higher than clomid’s rate of 43%. For patients with a BMI less than 30, the pregnancy rates were even higher, at 68.6% of patients getting pregnant with Femara, and 46.9% on Clomid.

As we all know, the time to pregnancy is important, and women got pregnant on Femara faster than they did on Clomid (with median cycles of 4 cycles on femara vs. 6 cycles on Clomid before pregnancy).

Live birth rate, of course, is the most important metric. In this respect, Femara showed a strong trend towards superiority, with a rate of 40% more than clomid. The absolute live birth rates were 49.3% for Femara and 35.1% for Clomid, but it’s important to note that while this trend was very strong, there wasn’t a big enough group in the study to show the result with statistical significance (the P value was 0.079).

As far as maternal and neonatal complication rates, there appeared to be no difference. There also weren’t enough people in the study to show a meaningful difference in the twin rate.

Results for the Crossover Group

For women who didn’t respond to either Clomid or Femara, then switched over, there was a relatively low pregnancy rate for both drugs as secondary treatments. The authors raise the possibility that this could indicate a cross-resistance between the two drugs.

Study Limitations

The main limitation to this study is the size -- we really wish they’d had more patients so that some of the most important findings and indicators (like the live birth rate) met statistical significance instead of just showing strong trends.

Also, the study was conducted in Europe, on a predominantly caucasian patient base, with a small group of South Asian women, so it’s not fully representative for a US population.

Overall, though, this was a strong study design, with findings that will likely be helpful to many doctors and patients as they contemplate the first line treatment for inducing ovulation amongst PCOS patients.